Myeloid-Derived Suppressor Cells: A Multifaceted Accomplice in Tumor Progression

Abstract

Myeloid-derived suppressor cell (MDSC) is a heterogeneous population of immature myeloid cells, has a pivotal role in negatively regulating immune response, promoting tumor progression, creating pre-metastases niche, and weakening immunotherapy efficacy. The underlying mechanisms are complex and diverse, including immunosuppressive functions (such as inhibition of cytotoxic T cells and recruitment of regulatory T cells) and non-immunological functions (mediating stemness and promoting angiogenesis). Moreover, MDSC may predict therapeutic response as a poor prognosis biomarker among multiple tumors. Accumulating evidence indicates targeting MDSC can reverse immunosuppressive tumor microenvironment, and improve therapeutic response either single or combination with immunotherapy. This review summarizes the phenotype and definite mechanisms of MDSCs in tumor progression, and provide new insights of targeting strategies regarding to their clinical applications.

Tissue-Resident Innate Immune Cell-Based Therapy: A Cornerstone of Immunotherapy Strategies for Cancer Treatment

“…In pathological conditions, such as infectious diseases, cancers or autoimmune disorders, deregulation on myeloid differentiation occurs, which, combined with a persistent stimulation of myelopoiesis, results in the expansion of MDSCs ( Consonni et al, 2019 ; Lim et al, 2020 ). This deregulated generation and expansion of immunosuppressive MDSCs is promoted by a series of cytokines, such as GM-CSF, VEGF, IL-1β, IL-6, and IL-10 ( Cheng et al, 2021 ). Significantly increased immature myeloid cells have been observed in the bone marrow and peripheral blood of patients with cancer ( Cheng et al, 2021 ), and the presence of enriched MDSCs have been related to poor prognosis for multiple types of cancer ( Jiang et al, 2015 ; Tian et al, 2015 ; De Cicco et al, 2020 ).…”

“…This deregulated generation and expansion of immunosuppressive MDSCs is promoted by a series of cytokines, such as GM-CSF, VEGF, IL-1β, IL-6, and IL-10 ( Cheng et al, 2021 ). Significantly increased immature myeloid cells have been observed in the bone marrow and peripheral blood of patients with cancer ( Cheng et al, 2021 ), and the presence of enriched MDSCs have been related to poor prognosis for multiple types of cancer ( Jiang et al, 2015 ; Tian et al, 2015 ; De Cicco et al, 2020 ). In fact, throughout the entire pathological process that leads to tumor formation, MDSCs increase up to10-fold and migrate to the periphery, exerting their suppressor activity interfering with the normal functions of circulating T and other immune cells involved in the anti-tumor immunity ( Safarzadeh et al, 2019 ; Nakamura and Smyth, 2020 ; Ma et al, 2022 ).…”

“…MDSCs mediate immunosuppressive effects under oxidative stress, producing reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). Increased ROS production induces damages on adaptive immune response by interfering with TCR CD3ζ expression, which acts on IFN-γ expression, hampering activation, viability and proliferation of T cells ( Belikov et al, 2015 ; Ohl and Tenbrock, 2018 ; Cheng et al, 2021 ). MDSCs express nitrogen-oxygen synthase 2 (iNOS).…”

“…Additionally, in tumor cell aggregation sites enriched with MDSCs, NO reacts with superoxide forming the RNS, namely peroxynitrite, a strong nitrifying agent. It can nitrate tyrosine residues in T cell receptor, inducing reduced IL-2 production with a consequent impaired T cell activation and proliferation ( Bentz et al, 2000 ; Cobbs et al, 2003 ; Szabo et al, 2007 ; Gabrilovich et al, 2012 ; Cheng et al, 2021 ) ( Feng et al, 2018 ). Besides, peroxynitrite can modify TCR conformational flexibility affecting its interaction with MHC class I molecules, causing the decreased response of cytotoxic CD8 T cells to antigen-specific stimulation ( Nagaraj et al, 2007 ).…”

“…In response to tumor microenvironment, MDSCs acquire the ability to produce multiple immunosuppressive molecules, such as cytokines, chemokines, and growth factors ( Lechner et al, 2010 ). The tumor microenvironment is characterized by high levels of IL-10 and MDSCs are the principal producers of this cytokine ( Cheng et al, 2021 ) IL-10, in turn, strengthens the immunosuppressive ability of MDSCs in a vicious cycle, by upregulating the expression of different immunosuppressive molecules ( Xiu et al, 2015 ; Lamichhane et al, 2017 ). IL-10 produced by MDSCs induce increased expression of lymphocyte activation gene 3 (LAG3) and the consequent decreased IL-2, IL-12, and IFNγ secretion by T cells, which hampered their proliferation and anti-tumor activity ( Vuk-Pavlovic et al, 2010 ; Li et al, 2015 ).…”